Center for Translational and Advanced Animal Research on Human Diseases, Division of Developmental Neuroscience, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan.
Dev Biol. 2010 Aug 15;344(2):658-68. doi: 10.1016/j.ydbio.2010.05.492. Epub 2010 May 24.
Epithelial-mesenchymal transition (EMT) permits neural crest cells to delaminate from the epithelial ectoderm and to migrate extensively in the embryonic environment. In this study, we have identified ATF4, a basic-leucine-zipper transcription factor, as one of the neural crest EMT regulators. Although ATF4 alone was not sufficient to drive the formation of migratory neural crest cells, ATF4 cooperated with Sox9 to induce neural crest EMT by controlling the expression of cell-cell and cell-extracellular matrix adhesion molecules. This was likely, at least in part, by inducing the expression of Foxd3, which encodes another neural crest transcription factor. We also found that the ATF4 protein level was strictly regulated by proteasomal degradation and p300-mediated stabilization, allowing ATF4 protein to accumulate in the nuclei of neural crest cells undergoing EMT. Thus, our results emphasize the importance of the regulation of protein stability in the neural crest EMT.
上皮-间充质转化（EMT）使神经嵴细胞从上皮外胚层分离并在胚胎环境中广泛迁移。在这项研究中，我们已经确定 ATF4（一种碱性亮氨酸拉链转录因子）是神经嵴 EMT 调节因子之一。尽管 ATF4 本身不足以驱动迁移性神经嵴细胞的形成，但 ATF4 与 Sox9 合作通过控制细胞-细胞和细胞-细胞外基质粘附分子的表达诱导神经嵴 EMT。这可能至少部分是通过诱导 Foxd3 的表达来实现的，Foxd3 编码另一种神经嵴转录因子。我们还发现 ATF4 蛋白水平受到蛋白酶体降解和 p300 介导的稳定化的严格调节，允许 ATF4 蛋白在经历 EMT 的神经嵴细胞的核内积累。因此，我们的结果强调了蛋白质稳定性调节在神经嵴 EMT 中的重要性。
